Neuroimmune signaling at the brain borders

Abstract

The central nervous system has traditionally been viewed as an immune privilege site with increased tolerance towards antigens that would induce rejection and limited immune responses against CNS antigens. 1 Sir Peter Medawar established this concept when performing his transplantation experiments demonstrating delayed rejection of skin graft in the brain. 2 He postulated that the immune privilege function of the brain arose primarily from (i) lack of drainage of CNS antigens to mount immune responses; (ii) isolation of the brain from peripheral infiltration through the blood brain barrier; and (iii) the relative absence of antigen presenting cells within the CNS. However, further studies demonstrated that rather than isolation and ignorance of the CNS by the immune system, it is rather tightly regulated interactions between immune cells and the CNS that control the apparent immune privilege status of the brain. 3,4 Likely, these controlled interactions are in place to limit neuronal damages while ensuring protection of the brain from infections and facilitate tissue repair.The anatomical sites where most of these interactions appear to take place are particularly located at the borders of the CNS. While the brain parenchyma is virtually devoid of immune cells, with exception of microglia and mast cells, its borders are populated with numerous innate and adaptive immune cells that actively communicate with the periphery to ensure surveillance and protection of the CNS.Yet we still know very little about the establishment, maintenance, and function of these brain borders. New technical advances and a deeper understanding of neuroimmune interactions are driving the field toward the definition of compartmentalized interactions between the brain and the immune system to allow for synergic control and maintenance of brain function in health and disease.Here, we will discuss the establishment and maintenance of the three primary brain borders, the meninges, the choroid plexus, and the blood brain barrier. We then dive into the described roles of the

Inflammasome activation in traumatic brain injury and Alzheimer's disease

“…The CNS environment has been traditionally considered to be immunologically privileged [27,28]. The blood-brain barrier (BBB), numerous antigen presenting cells, and a wide range of anti-inflammatory modulators participate in the brain"s immune response in which inflammation is highly regulated [27].…”

“…The blood-brain barrier (BBB), numerous antigen presenting cells, and a wide range of anti-inflammatory modulators participate in the brain"s immune response in which inflammation is highly regulated [27]. Recent studies identified that a large array of neuroimmune interactions occurs at the CNS borders in the meningeal lymphatic system and that dysfunction of this system exacerbates TBI pathologies [28,29]. Of all these mechanisms, microglia have been identified as key players in the CNS response to trauma.…”

Inflammatory processes in the prefrontal cortex induced by systemic immune challenge: Focusing on neurons

“…If the four hallmarks of CNS inflammation (elevated levels of proinflammatory cytokines, microglial activation, immune cell infiltration, and local tissue damage) can be identified, then the tissue response can be termed as neuroinflammation ( Estes and McAllister, 2014 ). Peripheral immune activation signals to the CNS mainly via the blood-brain barrier (BBB) and other brain borders (meninges, choroid plexus) ( Matsumura and Kobayashi, 2004 ; Frederick et al, 2022 ), however, BBB-independent pathways (e.g., circumventricular organs and vagal afferents) also contribute to the neuroimmune communication ( Quan, 2008 ). Inflammatory signaling at the BBB requires all cell types of the neurovascular unit (NVU), and involves both physiological (e.g., cytokine, chemokine, and prostaglandin E 2 signaling) and pathological (e.g., BBB disruption and leakage during severe inflammation) mechanisms leading to a proinflammatory tissue environment in the brain parenchyma ( Matsumura and Kobayashi, 2004 ; Banks et al, 2015 ; Tohidpour et al, 2017 ).…”

An introduction to neuroimmunology

“…The first few reviews in this special issue introduce some of the unique anatomical features of the CNS and further highlight how they uniquely contribute to the regulation of neuroimmune responses. In the first review of the series, Dr. Louveau and colleagues provide a comprehensive overview of the immunological properties of the meninges, which is a thin membranous structure positioned between the skull and brain parenchyma that houses a rich collection of immune cells as well as the CNS lymphatics 3 . In this review article, they first outline key components of meningeal lymphatic development, function, and physiology.…”

“…In the first review of the series, Dr. Louveau and colleagues provide a comprehensive overview of the immunological properties of the meninges, which is a thin membranous structure positioned between the skull and brain parenchyma that houses a rich collection of immune cells as well as the CNS lymphatics. 3 In this review article, they first outline key components of meningeal lymphatic development, function, and physiology. Next, they summarize an exciting body of recent literature which defines novel roles for defective brain lymphatic drainage in a spectrum of neurological disorders including Alzheimer's disease, multiple sclerosis (MS), and traumatic brain injury.…”